On April 17, 2023 Vincerx Pharma, Inc. (Nasdaq: VINC), a biopharmaceutical company aspiring to address the unmet medical needs of patients with cancer through paradigm-shifting therapeutics, reported a poster of preclinical data of VIP236 monotherapy treatment in PDX and metastatic PDX mouse models across several tumor types at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Vincerx Pharma, APR 17, 2023, View Source [SID1234630180]).

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VIP236 is a first-in-class SMDC with a tailored design to efficiently treat patients with aggressive and metastatic cancer. VIP236 binds to activated αVβ3 integrin, allowing specific homing to the tumor, and is efficiently cleaved by neutrophil elastase (NE). Both proteins are present in the tumor microenvironment (TME), are highly expressed in advanced metastatic tumors, and are associated with poor prognosis. Anticancer activity occurs after a specific and targeted release of an optimized CPT payload by NE in the TME. Once the optimized CPT payload penetrates and accumulates in the cell, it inhibits topoisomerase 1 (TOP1), causing DNA damage and leading to cell death. The novel optimized CPT payload of VIP236 was designed for high permeability with low active efflux potential to overcome transporter-mediated resistance observed with SN38, the active metabolite of irinotecan, which is also a CPT.

"The preclinical data presented at AACR (Free AACR Whitepaper) demonstrate that VIP236 had potent and durable antitumor activity in multiple mouse models implanted with tumor cells from cancer patients," said Ahmed Hamdy M.D., Chief Executive Officer of Vincerx. "VIP236 treatment was efficacious in a PDX non-small cell lung cancer model, including durable complete responses (CRs). Additionally, we observed significant tumor growth inhibition in a PDX colorectal cancer (CRC) liver metastasis model and significantly reduced lung and brain metastasis in a PDX orthotopic triple negative breast cancer (TNBC) model. Most notably, in gastric PDX and cell line-derived cancer models, VIP236 showed significant tumor growth inhibition compared with ENHERTU, an approved antibody-drug conjugate (ADC), independent of HER2 status. We know ENHERTU works in HER2 low breast cancer, so we’re encouraged to see our SMDC showing improved in vivo efficacy not just in HER2 high but also in HER2 low and HER2 negative gastric models. It’s important to note that showing this type of activity in PDX models is impressive, since these models are representative of the heterogeneity of human cancer and more meaningful than results seen in cell lines."

Dr. Hamdy continued, "The results presented at AACR (Free AACR Whitepaper), together with our previous findings showing that the anticancer potency of VIP236 can deliver up to 40 times more drug to the cancer while sparing surrounding tissues and normal organs, suggest that VIP236 has the potential to provide new treatment options for patients across various aggressive tumor types. We are excited with the continued progress of our bioconjugation platform and have started dosing the first cohort in our Phase 1 VIP236 dose-escalation study in patients with advanced solid tumors."

Key Presentation Highlights:
Poster presentation, titled, VIP236: A small molecule drug conjugate with an optimized camptothecin payload has significant activity in patient-derived and metastatic cancer models, presented by Beatrix Stelte-Ludwig, Ph.D., Vincerx Pharma GmbH, Monheim, Germany, include:

In an orthotopic metastatic breast cancer PDX model, immunohistochemistry analysis revealed an increase of αvβ3 and elastase staining after VIP236 treatment, while TOP1 expression remained stable. These results suggest VIP236 has potential antineoplastic activity across various advanced and metastatic cancers.
The mechanism of action of VIP236’s optimized CPT is characterized by TOP1 inhibition, which leads to DNA damage and, ultimately, cell death. DNA damage can be measured by phosphorylation of ɣH2Ax.
Time- and treatment-dependent phosphorylation of ɣH2Ax cells from the SNU16 cell line derived mouse model confirmed on-target TOP1 inhibition from the liberated optimized CPT payload derived from VIP236 and subsequent DNA damage.

VIP236 was efficacious in a PDX non-small cell lung cancer (NSCLC) model, with durable CRs. Partial responses and stable diseases were observed in PDX colon, renal, and TNBC models. Additionally, VIP236 treatment induced significant tumor growth inhibition in a PDX CRC liver metastatic model and significant reduction in lung and brain metastasis in a PDX orthotopic TNBC model. The reduction of brain metastases suggests successful VIP236 penetration of the blood-brain barrier.

In gastric PDX cancer models, VIP236 treatment showed significant tumor growth inhibition compared with the approved anti-HER2 ADC, ENHERTU (trastuzumab deruxtecan), independent of HER2 expression levels. Similar results were observed in a cell line-derived mouse model (HER2neg SNU16).
VIP236 is currently being evaluated in a first-in-human Phase 1 dose-escalation study in patients with advanced solid tumors (NCT05712889).

The poster can be accessed on the presentations section of the Vincerx website.

On April 17, 2023 Vincerx Pharma, Inc. (Nasdaq: VINC), a biopharmaceutical company aspiring to address the unmet medical needs of patients with cancer through paradigm-shifting therapeutics, reported a poster of preclinical data on novel integrin αvβ3-targeted small molecule drug conjugates (SMDCs) at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Vincerx Pharma, APR 17, 2023, View Source [SID1234630179]).

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Vincerx’s next-generation modular bioconjugation platform is designed to effectively target tumors with different modalities, including SMDCs and antibody-drug conjugates (ADCs). Our next-generation bioconjugation technology overcomes many of the known challenges of first-generation conjugation platforms and has shown increased safety and efficacy in relevant whole animal models. The platform consists of novel linker chemistries for tumor specific payload release; a toolbox of potent payload classes with novel modes of action to address a broad range of cancer targets; and tunable features that allow for optimization of the payload’s physiochemical profile to match target tumor biology.

"The preclinical data presented at AACR (Free AACR Whitepaper) demonstrate our ability to synthesize and characterize novel SMDCs," said Ahmed Hamdy M.D., Chief Executive Officer of Vincerx. "The data showed high elastase-dependent potency and cytotoxicity across several cancer cell lines. Furthermore, the data demonstrate excellent plasma stability in rats with low plasma clearance from several αvβ3 conjugates."

Dr. Hamdy continued, "Based on these results, the large scope of potential payloads and tolerated conjugation chemistries gives rise to a versatile strategy for selective delivery of payloads to the tumor microenvironment that does not require the tumor target to internalize. Furthermore, these encouraging results demonstrate the extensive scientific expertise of the Vincerx team and our commitment to discovering and developing paradigm-shifting conjugates for patients with cancer. We are excited about the potential expansion of our bioconjugation platform and continue to evaluate linker variations with in vivo studies across different payload classes."

Key Presentation Highlights:
Poster presentation, titled, Synthesis and characterization of novel small molecule drug conjugates with different payloads designed to be released in tumor microenvironment by neutrophil elastase, presented by Hans-Georg Lerchen, Ph.D., Vincerx Pharma GmbH, Monheim, Germany, include:

Imaging studies with fluorescent conjugates indicate efficient tumor homing in the tumor microenvironment of the αvβ3 binder and tumor-associated cleavage by neutrophil elastase (NE).
An optimized camptothecin (CPT; topoisomerase inhibitor), P-TEFbi (CDK9/CycT inhibitor) and kinesin spindle protein inhibitor (KSPi) were successfully converted into αvβ3-targeted SMDCs (VIP550, VIP280, and VIP1339, respectively) using different chemical handles (alcohol, sulfoximine and primary amine).
NE-cleavable linkers show high elastase-dependent potency with IC50 values of αvβ3 conjugates VIP550, VIP280 and VIP1339 in the nanomolar range across several cancer cell lines (786-0, HT29, NCI-H292, and SUM149) reaching similar potency as compared with the respective payloads alone.

αvβ3 conjugates VIP280, VIP550 and VIP1339 demonstrated excellent plasma stability and elastase-mediated release of CPT, P-TEFbi and KSPi payloads in rat plasma as well as in buffer at pH7.4.

Plasma clearance of all 3 small molecule drug αvβ3 conjugates was low with clearance being in the following rank ordering: VIP1339 > VIP550 > VIP280. Half-life was longer for SMDCs with the lowest clearance estimates. The ratio between AUC of the payload and parent SMDC was decreasing in the order of VIP280 > VIP550 > VIP1339. A 15-fold reduction in this ratio between VIP280 and VIP550 suggest a large increase in in vivo stability of the payload linker for VIP550 compared with VIP280.

Strong in vivo efficacy was shown with the SMDC VIP550 with a CPT payload in the MX1 TNBC mouse model. VIP550 monotherapy exhibits tumor regression in the 20 mg/kg intravenous 2 days on/5 days off treatment schedule (PR: 12/12). Once weekly application of VIP550 achieved stable disease (T/C: 0.34) and was slightly less efficacious compared with VIP236 (T/C: 0.24). No significant impact on mean body weight of mice was observed, indicating good tolerability of VIP550 and VIP236.

The poster can be accessed on the presentations section of the Vincerx website.

On April 17, 2023 Veracyte, Inc. (Nasdaq: VCYT) reported that new data published in European Urology Oncology suggest the Decipher Prostate Genomic Classifier could help identify prostate cancer patients who have micrometastatic disease (difficult-to-detect tumor cells that extend beyond the prostate) and who may therefore benefit from systemic treatment intensification (Press release, Veracyte, APR 17, 2023, View Source [SID1234630178]). The data show that, in men with high-risk and very high-risk disease, Decipher Prostate scores are highly correlated with upstaging predictions made by a clinical algorithm shown to predict prostate-specific membrane antigen (PSMA) positron emission tomography (PET) positivity.

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"Prostate cancer patients with clinically high-risk and very high-risk disease are prone to treatment failure due to micrometastatic disease that was not detected at the time of initial presentation, so it is imperative that we have tools to accurately identify these patients and intensify their treatment accordingly," said Amar U. Kishan, vice chair of Clinical and Translational Research and chief of the Genitourinary Oncology Service, UCLA Jonsson Comprehensive Cancer Center, and an investigator for the study. "Our findings suggest that a high Decipher Prostate score is highly correlated with the risk of having disease outside the prostate identified on advanced molecular imaging. These patients are likely to benefit from upfront systemic treatment intensification. Ongoing clinical trials are designed to prove this."

The 22-gene Decipher Prostate Genomic Classifier provides a score ranging from 0 to 1, categorized as low (<0.45), intermediate (0.45-0.60) and high risk (>0.60) of metastasis. It is the most validated prognostic biomarker for identifying metastatic disease risk among individuals with prostate cancer to help determine who may benefit from treatment intensification. It is currently being evaluated for its role as a predictive biomarker to guide systemic therapy intensification or deintensification in two large, Phase 3 clinical trials (NRG-GU009, NRG-GU010).

In the current study, researchers sought to quantify the association between the risk of upstaging on PSMA PET using a validated clinical algorithm for PSMA PET positivity developed by researchers at UCLA, and the Decipher Prostate score. Using data from 4,625 prostate cancer patients who met the criteria for NCCN high-risk or very high-risk disease or met the high-risk criteria for the STAMPEDE clinical trial, they calculated the probability of upstaging on PSMA PET using the established, validated clinical nomogram, and correlated this risk and individual patients’ Decipher Prostate scores.

The researchers found that there was a significant correlation between patients’ Decipher Prostate scores and the risk of upstaging on PSMA PET, and that high Decipher scores were especially enriched in patients at the highest risk of harboring disease outside their prostate. Accordingly, these patients would be more likely to benefit from systemic treatment intensification as compared to local therapy.

"These findings reinforce the evidence supporting the Decipher Prostate test’s ability to help inform treatment decision-making at initial prostate cancer diagnosis. We look forward to long-term data from ongoing, prospective trials such as NRG-GU009 to help verify the prognostic and predictive power of the Decipher Prostate test to guide treatment intensification or deintensification in patients with high-risk prostate cancer," said Elai Davicioni, Ph.D., Veracyte’s medical director for Urology.

On April 17, 2023 Tempest Therapeutics, Inc. (Nasdaq: TPST), a clinical-stage oncology company developing first-in-class1 therapeutics that combine both targeted and immune-mediated mechanisms, reported that new data from its TPST-1120 and TREX1 programs were highlighted in two poster presentations at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting taking place April 14-19, 2023 in Orlando, FL (Press release, Tempest Therapeutics, APR 17, 2023, View Source [SID1234630177]).

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The presentation for TPST-1120, a clinical-stage oral selective PPAR⍺ antagonist, highlighted new translational biomarker findings from the completed monotherapy and nivolumab combination therapy dose escalation Phase 1 trial showing on-target changes in gene signatures in the peripheral blood that were dependent upon drug exposure levels. In addition, distinct on-target changes in both lipid profile and NF-κB pathway regulated immune response gene signatures were observed in patients who achieved a RECIST response, compared with non-responders, following treatment with TPST-1120 and nivolumab.

The presentation for Tempest’s preclinical TREX1 inhibitor program, designed for tumor-selective activation of the STING pathway, is the first public demonstration of human TREX1 enzyme—TREX1 inhibitor X-ray co-crystal structures, which has facilitated the development of potent and specific TREX1 inhibitors with drug-like properties. Lead series molecules resulting from this activity demonstrated therapeutic benefit in tumor-bearing preclinical models.

"We are very excited to report these significant advances in the TPST-1120 and TREX1 programs," said Tom Dubensky, Ph.D., president of Tempest. "We look forward to the further clinical development of TPST-1120, potentially in multiple oncology indications, and are working to develop a TREX1 inhibitor to begin human clinical trials with this differentiated approach designed to selectively activate the STING pathway broadly in advanced metastatic disease."

About TPST-1120

TPST-1120 is an oral, small molecule, selective PPAR⍺ antagonist. Tempest’s preclinical data suggest that TPST-1120 can kill tumor cells directly and target suppressive immune pathways in the tumor microenvironment. Both types of targeted cells can be dependent on fatty acid metabolism, which is regulated by the PPAR⍺ transcription factor. In extensive non-clinical studies, TPST-1120 as a monotherapy or in combination with other anti-cancer drugs resulted in significant reductions in tumor growth and stimulation of durable anti-tumor immunity. In a Phase 1 clinical trial in patients with heavily-pretreated advanced solid tumors, TPST-1120 as monotherapy and in combination with the PD-1 inhibitor, nivolumab, demonstrated tumor reduction (including according to RECIST criteria), as well as biomarker modulation. TPST-1120 was well-tolerated both as a monotherapy and in combination with nivolumab. In addition, enrollment has completed in a Phase 1b/2 clinical trail conducted with F. Hoffman La-Roche, evaluating TPST-1120 + atezolizumab + bevacizumab in a randomized head-to-head comparison to atezolizumab + bevacizumab in the first line treatment of patients with unresectable or metastatic HCC. Initial results from this randomized study are expected in the first half of 2023.

About TREX1

TREX1 is a cytoplasmic DNA exonuclease that is upregulated in tumor cells in response to tumor growth, genomic instability and therapeutic intervention. TREX1 is both a negative regulator of the cGAS/STING signaling pathway and a DNA repair enzyme. Orally available TREX1 inhibitors are expected to both selectively inhibit tumor growth and induce tumor-specific immunity broadly against advanced metastatic disease. Tempest has shown proof of concept in animal models with this approach and is currently advancing a small molecule series through lead optimization.

On April 17, 2023 Sysmex Inostics Inc., a subsidiary of Japan’s Sysmex Corporation and Baltimore-based biotechnology firm and CLIA-certified lab, reported that it is exhibiting at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 in Orlando, FL from April 16, 2023, through April 19, 2023 (Press release, Sysmex Inostics, APR 17, 2023, View Source [SID1234630176]). The company is exhibiting at "Booth 1325" to meet with the over 20,000 global cancer research professionals in attendance.
While at AACR (Free AACR Whitepaper), Sysmex Inostics will take applications for its Cancer Research Excellence Program (CREP) announced in February. Winning cancer researchers receive free testing services of the company’s Plasma-Safe-SeqS technology, breast cancer or RAS-RAF signaling pathway panels. The program is open to U.S. solid tumor researchers at academic, medical, non-profit or government organizations; acceptance of applications ends on April 30, 2023.

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"At Sysmex Inostics we value every person, decision, and molecule within the therapeutic research journey including at the academic bench," said Shinichi Sato, President, and CEO of Sysmex Inostics. "Our CREP extends our reach into the medical research market increasing the adoption of our sensitive liquid biopsy technology, Plasma-Safe-SeqS, while also advancing critical early scientific discoveries."

Showcases New BioPharma Market Offering

On April 13th the company announced a strategic partnership with Genomic Testing Cooperative (GTC), a molecular testing company in Irvine, CA, for Sysmex Inostics to commercialize GTC’s DNA and RNA next generation sequencing (NGS) services to BioPharma customers. The partnership synergizes GTC’s proprietary testing, genomic databases, artificial intelligence (AI) technology with Sysmex Inostics’ global commercial capabilities in BioPharma therapeutic development and highly sensitive Plasma-Safe-SeqS technology.

BioPharma researchers and patients now have access to the testing they need at every stage of the clinical trial process from Sysmex Inostics. GTC’s suite of genomic assays – Solid Tumor Profile Plus, Liquid Trace Solid Tumor Profile, Liquid Trace Hematology Profile, and Hematology Profile Plus – allows BioPharma researchers tissue and liquid biopsy solid tumors and hematology assay services while discovering new molecules. While Sysmex Inostics’ CLIA-validated Plasma-Safe-SeqS ultra-sensitive liquid biopsy technology allows BioPharma to expedite clinical trial patient enrollment knowing patients are being monitored with one of the most sensitive liquid biopsy tests on the market.

"At Sysmex Inostics we understand how drugs are developed and we know not one test fits all stages of the process. It was imperative to offer our BioPharma partners broader panels for their discovery work. Our new partnership with GTC for pan-cancer testing services and existing collaboration with QIAGEN, for CDx development and regulatory submission, gives us the ability to support the entire therapeutic development journey," said Sato.

GTC has established a network of cooperative testing facilities that enable testing in clinical settings and in support of BioPharma research products with available Medicare reimbursement. The companies will work jointly on improvements and new indications of the tests for use by researchers.